RESUMEN
The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.
Asunto(s)
Antivirales , Inhibidores de Proteasa de Coronavirus , Furanos , Antivirales/química , Antivirales/farmacología , Lactamas , Péptido Hidrolasas , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , SARS-CoV-2 , Furanos/química , Inhibidores de Proteasa de Coronavirus/químicaRESUMEN
The pregnane X receptor (PXR) regulates expression of proteins responsible for all three phases required for the detoxification mechanism, which include CYP450 enzymes, phase II enzymes, and multidrug efflux pumps. Therefore, PXR is a prominent receptor that is responsible for xenobiotic excretion and drug-drug interactions. Pyrimidinone 1 is an antagonist of the calcium sensing receptor (CaSR) and a strong activator of PXR. Repeat oral administration revealed diminished exposures over time, which prohibited further progression. A medicinal chemistry campaign was initiated to understand and abolish activation of PXR in order to increase systemic exposures. Rational structure-activity relationship investigations utilizing cocrystal structures and a de novo pharmacophore model resulted in compounds devoid of PXR activation. These studies culminated in the first orally active CaSR antagonist 8 suitable for progression. Cocrystallography, the pharmacophore model employed, and additional observations reported herein supported rational elimination of PXR activation and have applicability across diverse chemical classes to help erase PXR-driven drug-drug interactions.
RESUMEN
Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4â¯t limited ghrelin-induced food intake.
Asunto(s)
Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Administración Oral , Animales , Encéfalo/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/farmacología , Enlace de Hidrógeno , Indoles/química , Indoles/metabolismo , Concentración 50 Inhibidora , Ratones , Mutagénesis , Inhibidores de Proteínas Quinasas/metabolismoRESUMEN
Human fatty acid synthase (hFAS) is a complex, multifunctional enzyme that is solely responsible for the de novo synthesis of long chain fatty acids. hFAS is highly expressed in a number of cancers, with low expression observed in most normal tissues. Although normal tissues tend to obtain fatty acids from the diet, tumor tissues rely on de novo fatty acid synthesis, making hFAS an attractive metabolic target for the treatment of cancer. We describe here the identification of GSK2194069, a potent and specific inhibitor of the ß-ketoacyl reductase (KR) activity of hFAS; the characterization of its enzymatic and cellular mechanism of action; and its inhibition of human tumor cell growth. We also present the design of a new protein construct suitable for crystallography, which resulted in what is to our knowledge the first co-crystal structure of the human KR domain and includes a bound inhibitor.
Asunto(s)
3-Oxoacil-(Proteína Transportadora de Acil) Reductasa/metabolismo , Inhibidores Enzimáticos/metabolismo , Ácido Graso Sintasas/antagonistas & inhibidores , Pirrolidinas/metabolismo , Pirrolidinas/farmacología , Triazoles/metabolismo , Triazoles/farmacología , 3-Oxoacil-(Proteína Transportadora de Acil) Reductasa/química , Dominio Catalítico , Línea Celular Tumoral , Ácido Graso Sintasas/química , Humanos , Modelos Moleculares , Conformación Proteica , Difracción de Rayos XRESUMEN
OBJECTIVE: The purpose of this study was to establish the frequency of burnout among doctors of chiropractic in the United States. METHODS: Using a nonprobability convenience sampling methodology, we e-mailed the Maslach Burnout Inventory-Human Services Survey and a sociodemographic questionnaire to a randomized sample of licensed doctors of chiropractic (n = 8000). RESULTS: The survey return rate was 16.06%. Twenty-one percent of the participants had high emotional exhaustion (EE), 8% had low personal accomplishment, and 8% had high depersonalization. DISCUSSION: Significant differences (P < .001) were found in the level of EE, depersonalization, and personal accomplishment as a function of sex, time dedicated to clinical care and administrative duties, source of reimbursement, the type of practice setting, the nature of practitioners' therapeutic focus, the location of chiropractic college, self-perception of burnout, the effect of suffering from a work-related injury, the varying chiropractic philosophical perspectives, and the public's opinion of chiropractic. CONCLUSION: Although doctors of chiropractic in the United States who responded to the survey had a relatively low frequency of burnout, higher levels of EE remain workplace issues for this professional group.
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Agotamiento Profesional/epidemiología , Quiropráctica , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Encuestas y Cuestionarios , Estados Unidos , Adulto JovenRESUMEN
OBJECTIVE: The purpose of this case report is to describe the presentation of a patient with lumbosacral chordoma characterized by somatic chronic low back pain and intermittent sacral nerve impingement. CASE REPORT: A 69-year-old male presenting to an emergency department (ED) with low back pain was provided analgesics and muscle relaxants then referred for a series of chiropractic treatments. Chiropractic treatment included manipulation, physical therapy, and rehabilitation. After 3 times per week for a total of 4 weeks, re-examination showed little relief of his symptoms. His pain symptoms worsened and he presented to the ED for the second time. Magnetic resonance imaging was performed and revealed a high intensity mass. INTERVENTION AND OUTCOME: The soft tissue mass identified on magnetic resonance imaging was surgically removed. Shortly after the surgery, the patient developed post-operative bleeding and was returned to surgery. During the second procedure, he developed a post-operative hemorrhage related to the development of disseminated intravascular coagulation and subsequently died during the second procedure. A malignant lumbosacral chordoma was diagnosed on pathologic examination. CONCLUSION: This case report describes the presentation of a patient with lumbosacral chordoma presenting with musculoskeletal low back pain. Chordomas are rare with few prominent manifestations. An early diagnosis can potentially make a difference in morbidity and mortality. Due to its insidious nature, it is a difficult diagnosis and one that is often delayed.
RESUMEN
To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Estilbenos/química , Estilbenos/farmacología , Secuencia de Aminoácidos , Animales , Línea Celular , Humanos , Conformación Molecular , Datos de Secuencia Molecular , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/agonistas , Bibliotecas de Moléculas Pequeñas/farmacología , Factor Esteroidogénico 1/agonistas , Secuencia de Aminoácidos , Animales , Cristalografía por Rayos X , Células HEK293 , Humanos , Ligandos , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/metabolismo , Homología de Secuencia de Aminoácido , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Factor Esteroidogénico 1/química , Factor Esteroidogénico 1/metabolismo , Activación Transcripcional/efectos de los fármacosRESUMEN
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Quinolinas/química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Sitios de Unión , Glucemia/metabolismo , Cristalografía por Rayos X , Diabetes Mellitus Experimental/metabolismo , Perros , Transferencia Resonante de Energía de Fluorescencia , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Ligandos , Ratones , Conformación Molecular , Estructura Terciaria de Proteína , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
Solution-processed bulk heterojunction organic photovoltaic (OPV) devices have gained serious attention during the last few years and are established as one of the leading next generation photovoltaic technologies for low cost power production. This article reviews the OPV development highlights of the last two decades, and summarizes the key milestones that have brought the technology to today's efficiency performance of over 7%. An outlook is presented on what will be required to drive this young photovoltaic technology towards the next major milestone, a 10% power conversion efficiency, considered by many to represent the efficiency at which OPV can be adopted in wide-spread applications. With first products already entering the market, sufficient lifetime for the intended application becomes more and more critical, and the status of OPV stability as well as the current understanding of degradation mechanisms will be reviewed in the second part of this article.
Asunto(s)
Fulerenos/química , Polímeros/química , Energía Solar , Técnicas Electroquímicas/instrumentación , SemiconductoresRESUMEN
Repression of gene transcription by the nuclear receptor Rev-erbalpha plays an integral role in the core molecular circadian clock. We report the crystal structure of a nuclear receptor-co-repressor (N-CoR) interaction domain 1 (ID1) peptide bound to truncated human Rev-erbalpha ligand-binding domain (LBD). The ID1 peptide forms an unprecedented antiparallel beta-sheet with Rev-erbalpha, as well as an alpha-helix similar to that seen in nuclear receptor ID2 crystal structures but out of register by four residues. Comparison with the structure of Rev-erbbeta bound to heme indicates that ID1 peptide and heme induce substantially different conformational changes in the LBD. Although heme is involved in Rev-erb repression, the structure suggests that Rev-erbalpha could also mediate repression via ID1 binding in the absence of heme. The previously uncharacterized secondary structure induced by ID1 peptide binding advances our understanding of nuclear receptor-co-repressor interactions.
Asunto(s)
Co-Represor 1 de Receptor Nuclear/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/química , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Secuencia de Aminoácidos , Línea Celular , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Co-Represor 1 de Receptor Nuclear/química , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Alineación de SecuenciaRESUMEN
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
Asunto(s)
Pirrolidinas/química , Receptores de Progesterona/agonistas , Animales , Sitios de Unión , Carbamatos/química , Cristalografía por Rayos X , Canal de Potasio ERG1 , Endometriosis/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/metabolismo , Femenino , Humanos , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Receptores de Progesterona/metabolismo , Sulfonamidas/químicaRESUMEN
Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the "meta" channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators.
Asunto(s)
Amidas/química , Diseño de Fármacos , Receptores de Glucocorticoides/química , Amidas/metabolismo , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , FN-kappa B/metabolismo , Estructura Terciaria de Proteína , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/metabolismoRESUMEN
High throughput screening of the corporate compound collection led to the identification of a novel series of 2-amino-9-aryl-3-cyano-4-methyl-7-oxo-6,7,8,9-tetrahydropyrido[2',3':4,5]thieno[2,3-b]pyridine derivatives as selective PR agonists. Initial SAR exploration leading to potent and selective agonists 9 and 11, X-ray crystal structure of 9 bound to PR-LBD and preliminary developability data are described.
Asunto(s)
Piridinas/química , Piridonas/química , Receptores de Progesterona/agonistas , Tiofenos/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Humanos , Microsomas Hepáticos/metabolismo , Conformación Molecular , Piridinas/síntesis química , Piridinas/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Ratas , Receptores de Progesterona/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.
Asunto(s)
Pirrolidinas/química , Receptores de Progesterona/agonistas , Administración Oral , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Modelos Animales , Estructura Terciaria de Proteína , Pirrolidinas/administración & dosificación , Pirrolidinas/síntesis química , Ratas , Receptores de Progesterona/metabolismoRESUMEN
We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivity against hERG channel inhibition.
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Pirrolidinonas/química , Receptores de Progesterona/agonistas , Administración Oral , Animales , Sitios de Unión , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/metabolismo , Haplorrinos , Humanos , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacocinética , Ratas , Receptores de Progesterona/metabolismo , Relación Estructura-ActividadRESUMEN
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiofenos/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Humanos , Isoxazoles/farmacología , Naftalenos/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Tiofenos/farmacocinéticaRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Asunto(s)
Isoxazoles/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Cristalografía por Rayos X , Transferencia Resonante de Energía de Fluorescencia , Isoxazoles/química , Isoxazoles/farmacología , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibition of acetyl-CoA carboxylase (ACC) may prevent lipid-induced insulin resistance and type 2 diabetes, making the enzyme an attractive pharmaceutical target. Although the enzyme is highly conserved amongst animals, only the yeast enzyme structure is available for rational drug design. The use of biophysical assays has permitted the identification of a specific C-terminal truncation of the 826-residue human ACC2 carboxyl transferase (CT) domain that is both functionally competent to bind inhibitors and crystallizes in their presence. This C-terminal truncation led to the determination of the human ACC2 CT domain-CP-640186 complex crystal structure, which revealed distinctions from the yeast-enzyme complex. The human ACC2 CT-domain C-terminus is comprised of three intertwined alpha-helices that extend outwards from the enzyme on the opposite side to the ligand-binding site. Differences in the observed inhibitor conformation between the yeast and human structures are caused by differing residues in the binding pocket.
Asunto(s)
Acetil-CoA Carboxilasa/química , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/aislamiento & purificación , Acetil-CoA Carboxilasa/metabolismo , Acetiltransferasas/antagonistas & inhibidores , Secuencia de Aminoácidos , Sitios de Unión , Dicroismo Circular , Cristalografía por Rayos X , Ácidos Grasos/metabolismo , Polarización de Fluorescencia , Humanos , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Desnaturalización Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).